ID   UBP35_HUMAN             Reviewed;        1018 AA.
AC   Q9P2H5;
DT   10-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT   30-NOV-2010, sequence version 3.
DT   24-JAN-2024, entry version 167.
DE   RecName: Full=Ubiquitin carboxyl-terminal hydrolase 35;
DE            EC=3.4.19.12 {ECO:0000269|PubMed:26348204, ECO:0000269|PubMed:34438346, ECO:0000269|PubMed:37004621};
DE   AltName: Full=Deubiquitinating enzyme 35;
DE   AltName: Full=Ubiquitin thioesterase 35;
DE   AltName: Full=Ubiquitin-specific-processing protease 35;
GN   Name=USP35; Synonyms=KIAA1372, USP34;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), CATALYTIC ACTIVITY, AND TISSUE
RP   SPECIFICITY.
RX   PubMed=14715245; DOI=10.1016/j.bbrc.2003.12.050;
RA   Quesada V., Diaz-Perales A., Gutierrez-Fernandez A., Garabaya C., Cal S.,
RA   Lopez-Otin C.;
RT   "Cloning and enzymatic analysis of 22 novel human ubiquitin-specific
RT   proteases.";
RL   Biochem. Biophys. Res. Commun. 314:54-62(2004).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=Brain;
RX   PubMed=10718198; DOI=10.1093/dnares/7.1.65;
RA   Nagase T., Kikuno R., Ishikawa K., Hirosawa M., Ohara O.;
RT   "Prediction of the coding sequences of unidentified human genes. XVI. The
RT   complete sequences of 150 new cDNA clones from brain which code for large
RT   proteins in vitro.";
RL   DNA Res. 7:65-73(2000).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16554811; DOI=10.1038/nature04632;
RA   Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA   Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA   Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA   Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA   Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA   Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT   "Human chromosome 11 DNA sequence and analysis including novel gene
RT   identification.";
RL   Nature 440:497-500(2006).
RN   [4]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-613, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [5]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-613, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma, and Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [6]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=25915564; DOI=10.1080/15548627.2015.1034408;
RA   Wang Y., Serricchio M., Jauregui M., Shanbhag R., Stoltz T., Di Paolo C.T.,
RA   Kim P.K., McQuibban G.A.;
RT   "Deubiquitinating enzymes regulate PARK2-mediated mitophagy.";
RL   Autophagy 11:595-606(2015).
RN   [7]
RP   FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF CYS-450.
RX   PubMed=26348204; DOI=10.18632/oncotarget.4451;
RA   Liu C., Wang L., Chen W., Zhao S., Yin C., Lin Y., Jiang A., Zhang P.;
RT   "USP35 activated by miR let-7a inhibits cell proliferation and NF-kappaB
RT   activation through stabilization of ABIN-2.";
RL   Oncotarget 6:27891-27906(2015).
RN   [8]
RP   FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF CYS-450, AND INDUCTION BY
RP   FOXM1.
RX   PubMed=29449677; DOI=10.1038/s41467-018-03107-0;
RA   Park J., Kwon M.S., Kim E.E., Lee H., Song E.J.;
RT   "USP35 regulates mitotic progression by modulating the stability of Aurora
RT   B.";
RL   Nat. Commun. 9:688-688(2018).
RN   [9]
RP   FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF CYS-450.
RX   PubMed=34438346; DOI=10.1016/j.bbrc.2021.08.050;
RA   Wang W., Lin H., Zheng E., Hou Z., Liu Y., Huang W., Chen D., Feng J.,
RA   Li J., Li L.;
RT   "Regulation of survivin protein stability by USP35 is evolutionarily
RT   conserved.";
RL   Biochem. Biophys. Res. Commun. 574:48-55(2021).
RN   [10]
RP   FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, UBIQUITINATION, MUTAGENESIS OF
RP   CYS-450, AND INTERACTION WITH HSP90AA1.
RX   PubMed=37004621; DOI=10.1007/s00018-023-04740-9;
RA   Park J., Shin S.C., Jin K.S., Lim M.J., Kim Y., Kim E.E., Song E.J.;
RT   "USP35 dimer prevents its degradation by E3 ligase CHIP through auto-
RT   deubiquitinating activity.";
RL   Cell. Mol. Life Sci. 80:112-112(2023).
CC   -!- FUNCTION: Deubiquitinase that plays a role in different processes
CC       including cell cycle regulation, mitophagy or endoplasmic reticulum
CC       stress (PubMed:26348204, PubMed:29449677, PubMed:37004621). Inhibits
CC       TNFalpha-induced NF-kappa-B activation through stabilizing TNIP2
CC       protein via deubiquitination (PubMed:26348204). Plays an essential role
CC       during mitosis by deubiquitinating and thereby regulating the levels of
CC       Aurora B/AURKB protein (PubMed:29449677). In addition, regulates the
CC       protein levels of other key component of the chromosomal passenger
CC       complex (CPC) such as survivin/BIRC5 or Borealin/CDCA8 by enhancing
CC       their stability (PubMed:34438346). Regulates the degradation of
CC       mitochondria through the process of autophagy termed mitophagy
CC       (PubMed:25915564). {ECO:0000269|PubMed:25915564,
CC       ECO:0000269|PubMed:26348204, ECO:0000269|PubMed:29449677,
CC       ECO:0000269|PubMed:34438346, ECO:0000269|PubMed:37004621}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide
CC         and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-
CC         residue protein attached to proteins as an intracellular targeting
CC         signal).; EC=3.4.19.12; Evidence={ECO:0000269|PubMed:14715245,
CC         ECO:0000269|PubMed:26348204, ECO:0000269|PubMed:34438346,
CC         ECO:0000269|PubMed:37004621};
CC   -!- SUBUNIT: Homodimer (via C-terminal region). Interacts with HSP90AA1.
CC       {ECO:0000269|PubMed:37004621}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:25915564}.
CC       Mitochondrion {ECO:0000269|PubMed:25915564}. Note=Only associates with
CC       polarized mitochondria, and rapidly translocates to the cytosol during
CC       mitophagy. {ECO:0000269|PubMed:25915564}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q9P2H5-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q9P2H5-2; Sequence=VSP_040291;
CC   -!- TISSUE SPECIFICITY: Expressed in testis, pancreas and skeletal muscle.
CC       {ECO:0000269|PubMed:14715245}.
CC   -!- INDUCTION: By FOXM1 transcription factor.
CC       {ECO:0000269|PubMed:29449677}.
CC   -!- PTM: Ubiquitinated by CHIP/STUB1 in an HSP90-dependent manner; leading
CC       to proteasomal degradation. This ubiquitination can be reversed through
CC       auto-deubiquitinating activity. {ECO:0000269|PubMed:37004621}.
CC   -!- SIMILARITY: Belongs to the peptidase C19 family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=BAA92610.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; AJ586137; CAE51937.1; -; mRNA.
DR   EMBL; AB037793; BAA92610.1; ALT_INIT; mRNA.
DR   EMBL; AP002985; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   CCDS; CCDS41693.1; -. [Q9P2H5-1]
DR   RefSeq; NP_065849.1; NM_020798.2. [Q9P2H5-1]
DR   RefSeq; XP_011543489.1; XM_011545187.2. [Q9P2H5-2]
DR   RefSeq; XP_011543490.1; XM_011545188.2. [Q9P2H5-2]
DR   RefSeq; XP_016873541.1; XM_017018052.1.
DR   PDB; 5TXK; X-ray; 1.84 A; A=423-944.
DR   PDB; 7Q44; X-ray; 2.20 A; B/D/F=988-1002.
DR   PDBsum; 5TXK; -.
DR   PDBsum; 7Q44; -.
DR   AlphaFoldDB; Q9P2H5; -.
DR   SMR; Q9P2H5; -.
DR   BioGRID; 121613; 19.
DR   IntAct; Q9P2H5; 4.
DR   STRING; 9606.ENSP00000431876; -.
DR   BindingDB; Q9P2H5; -.
DR   ChEMBL; CHEMBL4630862; -.
DR   MEROPS; C19.059; -.
DR   iPTMnet; Q9P2H5; -.
DR   PhosphoSitePlus; Q9P2H5; -.
DR   BioMuta; USP35; -.
DR   EPD; Q9P2H5; -.
DR   jPOST; Q9P2H5; -.
DR   MassIVE; Q9P2H5; -.
DR   MaxQB; Q9P2H5; -.
DR   PaxDb; 9606-ENSP00000431876; -.
DR   PeptideAtlas; Q9P2H5; -.
DR   ProteomicsDB; 83817; -. [Q9P2H5-1]
DR   ProteomicsDB; 83818; -. [Q9P2H5-2]
DR   Antibodypedia; 31304; 96 antibodies from 23 providers.
DR   DNASU; 57558; -.
DR   Ensembl; ENST00000526425.1; ENSP00000434942.1; ENSG00000118369.13. [Q9P2H5-2]
DR   Ensembl; ENST00000529308.6; ENSP00000431876.1; ENSG00000118369.13. [Q9P2H5-1]
DR   GeneID; 57558; -.
DR   KEGG; hsa:57558; -.
DR   MANE-Select; ENST00000529308.6; ENSP00000431876.1; NM_020798.4; NP_065849.1.
DR   UCSC; uc001ozf.4; human. [Q9P2H5-1]
DR   AGR; HGNC:20061; -.
DR   CTD; 57558; -.
DR   DisGeNET; 57558; -.
DR   GeneCards; USP35; -.
DR   HGNC; HGNC:20061; USP35.
DR   HPA; ENSG00000118369; Low tissue specificity.
DR   neXtProt; NX_Q9P2H5; -.
DR   OpenTargets; ENSG00000118369; -.
DR   PharmGKB; PA134883706; -.
DR   VEuPathDB; HostDB:ENSG00000118369; -.
DR   eggNOG; KOG1864; Eukaryota.
DR   GeneTree; ENSGT00940000160942; -.
DR   HOGENOM; CLU_010910_0_0_1; -.
DR   InParanoid; Q9P2H5; -.
DR   OMA; RCKKLCD; -.
DR   OrthoDB; 227085at2759; -.
DR   PhylomeDB; Q9P2H5; -.
DR   TreeFam; TF324529; -.
DR   PathwayCommons; Q9P2H5; -.
DR   SignaLink; Q9P2H5; -.
DR   BioGRID-ORCS; 57558; 24 hits in 1156 CRISPR screens.
DR   ChiTaRS; USP35; human.
DR   GenomeRNAi; 57558; -.
DR   Pharos; Q9P2H5; Tbio.
DR   PRO; PR:Q9P2H5; -.
DR   Proteomes; UP000005640; Chromosome 11.
DR   RNAct; Q9P2H5; Protein.
DR   Bgee; ENSG00000118369; Expressed in secondary oocyte and 116 other cell types or tissues.
DR   ExpressionAtlas; Q9P2H5; baseline and differential.
DR   GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR   GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell.
DR   GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR   GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:FlyBase.
DR   GO; GO:0016579; P:protein deubiquitination; IDA:FlyBase.
DR   GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR   Gene3D; 3.90.70.10; Cysteine proteinases; 2.
DR   InterPro; IPR016024; ARM-type_fold.
DR   InterPro; IPR038765; Papain-like_cys_pep_sf.
DR   InterPro; IPR001394; Peptidase_C19_UCH.
DR   InterPro; IPR049407; Usp38-like_N.
DR   InterPro; IPR018200; USP_CS.
DR   InterPro; IPR028889; USP_dom.
DR   PANTHER; PTHR24006; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE; 1.
DR   PANTHER; PTHR24006:SF660; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE 35; 1.
DR   Pfam; PF00443; UCH; 1.
DR   Pfam; PF21246; Usp38-like_N; 1.
DR   SUPFAM; SSF48371; ARM repeat; 1.
DR   SUPFAM; SSF54001; Cysteine proteinases; 1.
DR   PROSITE; PS00972; USP_1; 1.
DR   PROSITE; PS00973; USP_2; 1.
DR   PROSITE; PS50235; USP_3; 1.
DR   Genevisible; Q9P2H5; HS.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Cytoplasm; Hydrolase; Mitochondrion;
KW   Phosphoprotein; Protease; Reference proteome; Thiol protease;
KW   Ubl conjugation; Ubl conjugation pathway.
FT   CHAIN           1..1018
FT                   /note="Ubiquitin carboxyl-terminal hydrolase 35"
FT                   /id="PRO_0000080665"
FT   DOMAIN          441..926
FT                   /note="USP"
FT   REGION          544..566
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          610..757
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          984..1011
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        669..707
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        722..738
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        450
FT                   /note="Nucleophile"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10092,
FT                   ECO:0000255|PROSITE-ProRule:PRU10093"
FT   ACT_SITE        862
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10092,
FT                   ECO:0000255|PROSITE-ProRule:PRU10093"
FT   MOD_RES         613
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18669648,
FT                   ECO:0007744|PubMed:23186163"
FT   VAR_SEQ         1..269
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:10718198"
FT                   /id="VSP_040291"
FT   VARIANT         236
FT                   /note="V -> M (in dbSNP:rs2510044)"
FT                   /id="VAR_057042"
FT   MUTAGEN         450
FT                   /note="C->A: Complete loss of catalytic activity."
FT                   /evidence="ECO:0000269|PubMed:29449677,
FT                   ECO:0000269|PubMed:37004621"
FT   MUTAGEN         450
FT                   /note="C->S: Complete loss of catalytic activity."
FT                   /evidence="ECO:0000269|PubMed:34438346"
FT   CONFLICT        224
FT                   /note="Missing (in Ref. 1; CAE51937)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        464
FT                   /note="D -> E (in Ref. 1; CAE51937)"
FT                   /evidence="ECO:0000305"
FT   HELIX           450..461
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   HELIX           463..470
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   HELIX           479..493
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   STRAND          496..499
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   HELIX           502..507
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   HELIX           521..549
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   HELIX           565..570
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   STRAND          572..580
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   TURN            581..583
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   STRAND          586..598
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   HELIX           761..768
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   STRAND          772..774
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   HELIX           776..778
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   STRAND          780..782
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   TURN            783..786
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   STRAND          787..789
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   STRAND          791..799
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   STRAND          802..808
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   STRAND          811..814
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   TURN            815..818
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   STRAND          819..822
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   STRAND          831..836
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   HELIX           838..840
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   STRAND          842..854
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   STRAND          856..860
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   STRAND          862..867
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   STRAND          891..894
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   STRAND          897..900
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   HELIX           903..912
FT                   /evidence="ECO:0007829|PDB:5TXK"
FT   STRAND          916..925
FT                   /evidence="ECO:0007829|PDB:5TXK"
SQ   SEQUENCE   1018 AA;  113405 MW;  79DECFF920B3666A CRC64;
     MDKILEAVVT SSYPVSVKQG LVRRVLEAAR QPLEREQCLA LLALGARLYV GGAEELPRRV
     GCQLLHVAGR HHPDVFAEFF SARRVLRLLQ GGAGPPGPRA LACVQLGLQL LPEGPAADEV
     FALLRREVLR TVCERPGPAA CAQVARLLAR HPRCVPDGPH RLLFCQQLVR CLGRFRCPAE
     GEEGAVEFLE QAQQVSGLLA QLWRAQPAAI LPCLKELFAV ISCAEEEPPS SALASVVQHL
     PLELMDGVVR NLSNDDSVTD SQMLTAISRM IDWVSWPLGK NIDKWIIALL KGLAAVKKFS
     ILIEVSLTKI EKVFSKLLYP IVRGAALSVL KYMLLTFQHS HEAFHLLLPH IPPMVASLVK
     EDSNSGTSCL EQLAELVHCM VFRFPGFPDL YEPVMEAIKD LHVPNEDRIK QLLGQDAWTS
     QKSELAGFYP RLMAKSDTGK IGLINLGNTC YVNSILQALF MASDFRHCVL RLTENNSQPL
     MTKLQWLFGF LEHSQRPAIS PENFLSASWT PWFSPGTQQD CSEYLKYLLD RLHEEEKTGT
     RICQKLKQSS SPSPPEEPPA PSSTSVEKMF GGKIVTRICC LCCLNVSSRE EAFTDLSLAF
     PPPERCRRRR LGSVMRPTED ITARELPPPT SAQGPGRVGP RRQRKHCITE DTPPTSLYIE
     GLDSKEAGGQ SSQEERIERE EEGKEERTEK EEVGEEEEST RGEGEREKEE EVEEEEEKVE
     KETEKEAEQE KEEDSLGAGT HPDAAIPSGE RTCGSEGSRS VLDLVNYFLS PEKLTAENRY
     YCESCASLQD AEKVVELSQG PCYLILTLLR FSFDLRTMRR RKILDDVSIP LLLRLPLAGG
     RGQAYDLCSV VVHSGVSSES GHYYCYAREG AARPAASLGT ADRPEPENQW YLFNDTRVSF
     SSFESVSNVT SFFPKDTAYV LFYRQRPREG PEAELGSSRV RTEPTLHKDL MEAISKDNIL
     YLQEQEKEAR SRAAYISALP TSPHWGRGFD EDKDEDEGSP GGCNPAGGNG GDFHRLVF
//